Myelodysplastic syndromes (MDS) are hematologic malignancies originating from a defective hematopoietic stem cell (HSC), and defined by blood cytopenias due to ineffective hematopoiesis, a predisposition to acute myeloid leukemia (AML), and genomic instability. We recently identified miR-146a, a microRNA that is part of the deleted segment of chromosome 5q in MDS (del(5q)). Reduced expression of miR-146a, either in del(5q) or normal karyotype MDS, results in increased protein expression of TRAF6, a key target of miR-146a and a mediator of innate immune signaling. Therefore, we hypothesize that chronic innate immune signaling (mediated by TRAF6) contributes to MDS and progression to AML in part by reprogramming the metabolic state of HSC. We also propose that innate immune pathway inhibition will suppress MDS- and AML-propagating cells. Based on these observations, we will (1) define the role of chronic innate immune signaling via TRAF6 in HSC during the progression from MDS to AML, (2) determine the oncogenic dependency of MDS/AML on TRAF6, and (3) investigate HSC metabolic reprograming in MDS HSC. The complexity of MDS and paucity of mouse models are obstacles to effectively treating this disease. The identification of TRAF6 mechanisms in MDS will impact diagnosis, molecular staging, and targeted therapy for MDS/AML, and illuminate a novel and clinically-relevant connection between TRAF6 and metabolic reprogramming via AKT and/or NF-?B in MDS.